Abstract Background Associations between disease duration and achieving remission are well established in Crohn’s disease (CD), but remain unclear in ulcerative colitis (UC)1-3. At the molecular level, oxidative phosphorylation and mitochondrial dysfunction have been linked to prolonged disease duration in CD, but not in UC4. Understanding molecular changes throughout the disease course is key to refine patient stratification and uncover pathways driving (sub)mucosal remodelling. Methods Inflamed colonic biopsies (eMayo ≥2; n = 5 bio-naive, n = 5 bio-experienced) were cultured ex vivo for 24h5 (n = 9/patient), subsequently RNA-sequenced (NovaSeq 6000; DESeq2), and analysed by Ingenuity Pathway Analysis (IPA) and cell type enrichment analysis by xCell6. Gene co-expression networks were identified via Weighted Gene Co-expression Network Analysis (WGCNA) (FDR 0.05) on all samples. Validation used active controls from the TRIESTE-UC cohort (n = 24; eMayo ≥2; split by disease duration 2.5 or 10 years7). Results Co-expression analysis of ex vivo biopsies identified 20 gene modules linked to distinct traits. Two modules - red (p = 6.2x10-11) and cyan (p = 2.1x10-5) - were negatively correlated with disease duration, independent of prior biological exposure (Fig1A). Both were enriched for immune regulatory pathways, including reduced “T cell activation” and “adaptive immune response” with longer disease duration (Fig1B). In contrast, the turquoise module (p = 0.048) associated positively with metabolic processes in disease duration (Fig1C). Cell type enrichment highlighted an overall reduced ImmuneScore, along reduced B- and T-cell type enrichment in long disease duration (FDR 0.001), while hierarchical clustering segregated samples with longer disease duration (Fig1D-E). Notably, endoscopic activity (eMayo) did not correlate with any of these modules. Validation using GSEA in the TRIESTE cohort confirmed a negative enrichment score (ES -0.65) for downregulated genes from the discovery cohort (Fig2A) and red module (ES -0.66), while the cyan module showed a mild negative ES (-0.29) (Fig2B). BANK1 was a leading-edge gene in the validation cohort (Log2FC -1.51, FDR 0.012; discovery Log2FC -2.29, FDR 5.93x10-19), and red module hubs IKZF1 (Log2FC -0.66; FDR 0.116) and IKZF3 (Log2FC -0.883; FDR 0.117) showed similar downregulation trends. Conclusion We identified reduced T cell, B cell, and adaptive immunity signatures in UC biopsies with longer disease duration, independent of inflammation or biological exposure. Key regulators included IZKF1 and IZKF3– drivers of Th17-Treg plasticity8 - and BANK1, modulating B cell-Treg interactions9. These findings highlight altered immune regulation along disease progression and suggest opportunities for duration-tailored therapeutic. References: 1. D’Haens et al., Lancet Gastroenterol Hepatol, 2025 2. Vermeire et al., JCC, 2024 3. Ben-Horin et al., Gastroenterology, 2022 4. Ibing et al., JCC, 2025 5. Giorio, Arnauts et al., abstract MP564, UEGW, Vienna, 2024 6. Aran et al., Genome Biology, 2017 7. Lenfant et al. abstract Tu1744, Gastroenterology 166-5,2024- ISSN 0016-5085 8. Ramón- Vázquez et al., Autoimmun Rev. 2025 9. Yang et al., Arthritis research & therapy, 2018 KA and LG are joint first authors Conflict of interest: Dr. Arnauts, Kaline: Research support by Galapagos NV. Grant support by FWO senior postdoctoral research grant. Giorio, Lorenzo: Research support from Galapagos NV Lenfant, Matthias: None Zadora, Ward: No conflicts of interest Abdurahiman, Saeed: None to declare Guedelha Sabino, João: Speaker’s fees: Lilly, Pfizer, Abbvie, Ferring, Falk, Takeda, Janssen, Fresenius, and Galapagos. Consultancy fees: Takeda, Pfizer, Janssen, Ferring, Fresenius, Abbvie, Galapagos, Celltrion, Pharmacosmos, and Pharmanovia. Research support: Galapagos, Viatris, and Eurogenerics. JS is supported by a Senior Clinical researcher grant from the Research foundation – Flanders. Ferrante, Marc: Research grants from AbbVie, EG Pharma, Celltrion, Janssen, Pfizer, Takeda and Viatris Consultancy fees from AbbVie, AgomAb Therapeutics, Boehringer Ingelheim, Celgene, Celltrion, Eli Lilly, Janssen-Cilag, MRM Health, Merck Sharp and Dohme, Pfizer, Takeda and ThermoFisher Speakers’ fees from AbbVie, Biogen, Boehringer Ingelheim, Dr Falk Pharma, Ferring, Janssen-Cilag, Merck Sharp and Dohme, Pfizer, Takeda, Truvion Healthcare and Viatris Vermeire, Séverine: Grant: AbbVie, Pfizer, Takeda, J&J, Galapagos Personal Fees: AbbVie - AbolerIS Pharma - AgomAb - Alimentiv - Arena Pharmaceuticals - AstraZeneca - Avaxia- BMS - Boehringer Ingelheim - Celgene - CVasThera - Dr Falk Pharma - Ferring - Galapagos - Genentech-Roche - Gilead - GSK - Hospira - Imidomics - Janssen - J&J - Lilly - Materia Prima - MiroBio - Morphic - MrMHealth - Mundipharma - MSD - Pfizer - Prodigest - Progenity - Promakhos Therapeutics - Prometheus - Robarts Clinical Trials - Second Genome - Shire - Surrozen - Takeda - Theravance - Tillots Pharma AG - Zealand Pharma - Other: AbbVie, MSD, Takeda, Ferring, Genentech/Roche, Shire, Pfizer Inc, Galapagos, Mundipharma, Verstockt, Bram: - Research support from AbbVie, Biora Therapeutics, Celltrion, Landos, Pfizer, Sanofi, Sossei Heptares/Nxera and Takeda. - Speaker’s fees from Abbvie, Agomab, Alfasigma, Biogen, Bristol Myers Squibb, Celltrion, Eli Lily, Falk, Ferring, Galapagos, Materia Prima, Johnson and Johnson, Pfizer, Sandoz, Takeda, Tillots Pharma, Truvion and Viatris. - Consultancy fees from Abbvie, Alfasigma, Alimentiv, Anaptys Bio, Applied Strategic, Astrazeneca, Atheneum, BenevolentAI, Biora Therapeutics, Boxer Capital, Bristol Myers Squibb, Domain Therapeutics, Eli Lily, Galapagos, Guidepont, Landos, Merck, Mirador Therapeutics, Mylan, Nxera, Inotrem, Ipsos, Johnson and Johnson, Pfizer, Sandoz, Sanofi, Santa Ana Bio, Sapphire Therapeutics, Sosei Heptares, Takeda, Tillots Pharma and Viatris. - Stock options Vagustim and Thethis Pharma.
Durbec et al. (2026) studied this question.